Environmental tobacco smoke (ETS) is a mixture of 85% cigarette sidestream smoke (SS) and 15% mainstream smoke (MS) exhaled by active smokers. Epidemiological studies suggest that "involuntary smokers" exposed to ETS are at risk to develop lung cancer. In strain A/J mice, exposed to SS for 5 months, followed by a 4 month recovery period in air, doubles the incidence and more than doubles the multiplicity of lung tumors. This is the first animal model that allows, in a practical way, to study the beneficial effects of chemopreventive agents and of mechanisms of lung tumorigenesis caused by tobacco smoke. It will be possible to examine whether lung tumor development induced by SS can be partially or totally prevented by agents that have been shown effective in the chemoprevention of lung tumors induced by individual constituents of tobacco smoke such as nitrosamines or polycyclic aromatic hydrocarbons. Strain A/J mice will be exposed to SS while at the same time being fed blocking agents (phenethyl isothiocyanate, PEITC and benzylisothiocyanate, BITC) or being treated with a suppressing agent (Bowman-Birk protease inhibitor). Additional studies will examine the possibility that in lung tumors produced by exposure to SS there is a shift from codon 12 to codon 61 mutations in the Ki-ras protooncogene. Possible modulation of phase I and phase II drug metabolizing enzymes and DNA adduct formation will be examined in animals exposed to SS and the chemopreventive agents. Dose-response studies should allow to obtain some information on the potency of SS as a pulmonary carcinogen. The experiments will provide information on the question whether it might be feasible to diminish or even eliminate development of lung cancer by "involuntary smoking" with specific chemopreventive agents.